Perspectives on the use of ceftolozane/tazobactam: a review of clinical trial data and real-world evidence

Resistance of bacterial pathogens to commonly used antibiotics is increasing worldwide at a concerning rate and is considered a critical public health issue [1–4]. In 2019, antibacterial resistance was the third leading cause of death globally, with an estimated 4.95 million deaths reported [5]. To address these escalating resistance rates, several initiatives have been developed over the past two decades. One collaborative, the 10 × '20 initiative by the Infectious Diseases Society of America (IDSA), led to the development of several new systemic antibacterial drugs to combat multidrug-resistant (MDR) bacteria [6]. In addition, the ‘Bad Bugs, No Drugs’ report published by the IDSA in 2004 proposed collaborative solutions for new antibiotic development [6,7]. Certain bacterial pathogens have been declared critical threats by public health authorities, including the clinically important Gram-negative pathogens MDR Pseudomonas aeruginosa, carbapenem-resistant P. aeruginosa and extended-spectrum β-lactamase (ESBL)-producing Enterobacterales [3,8]. There is a remaining unmet need to establish how newly developed antibacterial agents can fit into clinical practice and address the burden associated with Gram-negative pathogens, particularly MDR strains.

Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are common nosocomial infections with limited treatment options and are often caused by MDR P. aeruginosa [9–11]. HABP can be defined as pneumonia occurring at least 48 h after hospital admission and which was not present at the time of admittance [12]. Patients who require mechanical ventilation after developing HABP are diagnosed with ventilated HABP (vHABP) [13]. VABP is considered clinically different from vHABP, and patients with VABP represent a significant subset of patients with HABP. VABP is defined as pneumonia with onset after receipt of mechanical ventilation via an endotracheal tube for a minimum of 48 h. It is estimated to affect 10–20% of all hospitalized patients receiving mechanical ventilation [12]. MDR P. aeruginosa, including carbapenem-non-susceptible strains, is increasingly becoming a more common causative agent of HABP and VABP [9,10]. HABP and VABP are some of the most common healthcare-associated infections in the USA and Europe [11,14]. In these regions, most nosocomial pneumonia infections are caused by the Gram-negative pathogens P. aeruginosa (33% and 34%, respectively), Klebsiella pneumoniae (12% and 18%, respectively), and Escherichia coli (10% and 16%, respectively) [9,15].

P. aeruginosa, including MDR strains, is a major causative pathogen of HABP and VABP, and its prevalence is increasing in the USA, Europe, and many other parts of the world [10,16–19]. In Europe, 27–31% of P. aeruginosa isolates from patients hospitalized with pneumonia (including VABP) were MDR [9,10]. In hospitals in the USA between 2000 and 2019, MDR was identified in 13–32% of P. aeruginosa isolates, and up to 34% of MDR P. aeruginosa infections were identified as hospital-acquired [17,18,20,21].

P. aeruginosa often harbors multiple intrinsic or acquired resistance mechanisms to many common antipseudomonal agents and classes [15]. Mechanisms that contribute to MDR in P. aeruginosa include: hyperproduction of a chromosomal ampicillin C (AmpC; i.e., Pseudomonas-derived cephalosporinase [PDC]) [22], production of β-lactamases (including ESBLs and carbapenemases) [23]; mutations in outer membrane porin D (OprD), which functions to transport amino acids and is thought to facilitate the entry of carbapenem antimicrobial agents [24]; and mutations in regulators and/or repressors, resulting in the overproduction of bacterial efflux pumps (e.g., MexAB–OprM, MexCD–OprJ, and MexXY) that transport antibacterial agents out of the bacterial cell [25,26]. Studies in Europe and the USA have shown that isolates obtained from hospitalized patients with pneumonia had an incidence of MDR P. aeruginosa ranging from 13% to 31% [10,18,27,28].

The presence of MDR pathogens, including MDR P. aeruginosa, increases the likelihood of initial treatment failure for patients with HABP and VABP, adding to the already high morbidity and mortality risk associated with these infections [29–31]. To treat HABP and VABP successfully and improve patient survival, appropriate antibacterial agents that are effective against the causative pathogen should be initiated in a timely manner. In addition, appropriate dosages that can achieve optimal concentrations in pulmonary target tissue should be used [32]. This aspect is particularly relevant for critically ill patients who may have altered antimicrobial pharmacokinetics (PK) [33]. Carbapenems are a mainstay of treatment for HABP/VABP [34]. However, increased use of these agents has led to increased carbapenem-non-susceptibility in P. aeruginosa, which affects carbapenem treatment effectiveness [35]. Therefore, the development of regimens with alternative agents suitable for the treatment of MDR P. aeruginosa infections is an unmet medical need.

Ceftolozane/tazobactam (ZERBAXA^®, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA) is an intravenously (IV) administered β-lactam/β-lactamase inhibitor combination approved for the treatment of nosocomial pneumonia using a 3 g every 8 h (q8h) regimen for 8–14 days [36]. Ceftolozane/tazobactam is also indicated for other types of infection, including complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs), at half the dosing regimen (1.5 g q8h) required for treatment of nosocomial pneumonia. The recommended duration of treatment for ceftolozane/tazobactam in patients with cUTIs and cIAIs is 7 days and 4–14 days, respectively [36]. Ceftolozane is a novel anti-pseudomonal cephalosporin that has greater activity against P. aeruginosa compared with other anti-pseudomonal β-lactams. This is due to the stability of ceftolozane against AmpC β-lactamases (i.e., PDCs) that are intrinsically produced by P. aeruginosa [37]. In combination with the well-established β-lactamase inhibitor tazobactam, ceftolozane retains activity against the majority of resistance mechanisms commonly observed in P. aeruginosa [38] and ESBL-producing Enterobacterales [39].

This targeted literature review aims to summarize the evidence from clinical trials and real-world effectiveness studies of ceftolozane/tazobactam for the treatment of serious healthcare-associated Gram-negative infections, with a focus on critically ill patients with HABP and VABP.

Search strategy

A PubMed search for all articles including the terms ‘ceftolozane/tazobactam’ was performed.

Pharmacokinetics

Notable changes in antimicrobial PK may be observed in critically ill patients with nosocomial pneumonia, which may lead to unintentional underdosing of antibacterial agents and, consequently, poor clinical outcomes [32,40,41]. In patients with nosocomial pneumonia, drug exposure in the lungs is a crucial indicator of clinical outcomes associated with dosing regimens. Differences observed in drug PK and tissue distribution in critically ill patients can affect bronchopulmonary concentration [40]. Studies of intrapulmonary penetration in critically ill patients have demonstrated greater variability in the duration, magnitude, and variability of epithelial lining fluid (ELF) penetration concentrations compared with healthy patients [32,42]. This variability should be an important consideration for optimization of dosing regimens for certain infections, such as VABP, in which pathogens may have elevated minimum inhibitory concentration (MIC) levels [32].

The C_max and area under the curve (AUC) of ceftolozane/tazobactam increase proportionally to dose within a single-dose range of 250 mg to 3 g for ceftolozane and 500 mg to 1.5 g for tazobactam. In healthy adults with normal renal function, no sizeable accumulation of ceftolozane/tazobactam (1 g/0.5 g or 2 g/1 g) is observed following multiple 1-h IV infusions administered q8h for up to 10 days. The elimination half-life of ceftolozane or tazobactam is independent of dose [36].

Despite the variances of PK observed in critically ill patients, studies have indicated that ceftolozane/tazobactam is still effective at current recommended dosing regimens. A phase I trial assessed the bronchopulmonary penetration of ceftolozane/tazobactam in mechanically ventilated patients with pneumonia [40]. Plasma and bronchoalveolar lavage samples were collected from patients who received 4–6 doses of ceftolozane/tazobactam to determine plasma and ELF drug concentrations, respectively [40]. In this high-risk population, the adequate lung penetration levels for ceftolozane (∼50%) and tazobactam (62%) required to treat ceftolozane/tazobactam-susceptible respiratory pathogens was achieved [40]. ELF concentrations remained above the MIC threshold for 100% of the dosing interval (3 g/q8h) for both ceftolozane (>8 mg/l) and tazobactam (>1 mg/l), indicating that ceftolozane/tazobactam achieves PK/pharmacodynamic (PD) targets associated with efficacy at the site of pneumonia infection. Compared with previous results from healthy volunteers, high variability was observed in plasma and ELF results from critically ill patients included in this study [40].

In another study, the probability of target attainment (PTA) of ceftolozane and tazobactam in patients with HABP/VABP with normal and impaired renal function was assessed using the dosing regimens evaluated in the ASPECT-nosocomial pneumonia (NP) trial. Using established PK/PD targets of 30% of the interdose interval with free drug concentrations (ƒT) exceeding the MIC of 4 μg/ml (ƒT>MIC = 4 μg/ml) for ceftolozane and 20% ƒT exceeding the threshold concentration of 1 μg/ml (ƒT>CT = 1 μg/ml) for tazobactam, this analysis showed that, across the different renal function groups (mild, moderate and severe), plasma PTA was 100% for ceftolozane and >99% for tazobactam, and ELF PTA was >99% for ceftolozane and >87% for tazobactam [43]. These results support the currently recommended ceftolozane/tazobactam dosing regimens for HABP/VABP in patients with impaired renal function [43].

Clinical studies in patients treated with ceftolozane/tazobactam

The efficacy and safety of ceftolozane/tazobactam against several different pathogens has been demonstrated through three pivotal international, multicenter, phase III, randomized controlled clinical programs, namely ASPECT-cIAI, ASPECT-cUTI and ASPECT-NP. These similarly structured ASPECT trials were designed to assess the non-inferiority of ceftolozane/tazobactam against active comparators in patients >18 years of age [44–46].

Patients with cIAI and cUTI

Ceftolozane/tazobactam was approved in 2014 for the treatment of cIAI and cUTI, including pyelonephritis, in adults, and more recently in 2022, in pediatric patients [47]. Approval for these indications was based on the results from the ASPECT-cIAI and ASPECT-cUTI clinical trials, as well as subsequent pediatric phase II trials for each indication.

ASPECT-cIAI baseline characteristics

ASPECT-cIAI was a multi-center, double-blind, randomized, controlled trial that compared ceftolozane/tazobactam plus metronidazole with meropenem. Overall, 993 patients were randomized to receive ceftolozane/tazobactam plus metronidazole (n = 487) or meropenem (n = 506). Baseline demographic characteristics were similar between treatment groups. The most common origin of infection was the appendix, and the most common diagnosis was either abscess or appendiceal perforation [45].

ASPECT-cIAI treatment duration

Around half of patients in each treatment group received therapy for up to 7 days, and an additional 36.5% received treatment for up to 10 days. The maximum duration of therapy was 15 days [45].

ASPECT-cIAI efficacy

In ASPECT-cIAI, ceftolozane/tazobactam was non-inferior for the primary endpoint of clinical cure, with rates of 83.0% (n = 323/389) and 87.3% (n = 364/417) for ceftolozane/tazobactam plus metronidazole and 87.3% (n = 364/417) for meropenem [45]. Efficacy of ceftolozane/tazobactam for the treatment of cIAI has also been confirmed in Asian participants [48,49]. One phase III study by Sun et al. demonstrated non-inferiority of ceftolozane/tazobactam plus metronidazole versus meropenem in adult Chinese participants (N = 268), with clinical cure rates of 95.2% and 93.1%, respectively [48].

In a subgroup analysis of patients with P. aeruginosa infection at baseline, ceftolozane/tazobactam demonstrated potent in vitro activity and in vivo efficacy against P. aeruginosa. Clinical cure rates in the microbiologically evaluable population were 100% (n = 26/26) for ceftolozane/tazobactam plus metronidazole and 93.1% (n = 27/29) for meropenem [50].

ASPECT-cIAI safety

In the ASPECT-cIAI trial, the frequency of adverse events (AEs) was similar between ceftolozane/tazobactam plus metronidazole (44.0% [n = 212/482]) and meropenem (42.7% [n = 212/497]), and most AEs were mild to moderate in severity. The most common AEs, occurring in ≥2% of patients, were nausea and diarrhea. Drug-related AEs leading to discontinuation occurred in three patients (0.6%) in the ceftolozane/tazobactam plus metronidazole group and in four patients (0.8%) in the meropenem group. Serious AEs occurred in 8.1% (n = 39/482) and 7.2% (n = 36/497) of patients in the ceftolozane/tazobactam plus metronidazole and meropenem groups, respectively. Mortality rates were 2.3% in the ceftolozane/tazobactam plus metronidazole group and 1.6% in the meropenem group. No deaths were considered by investigators to be related to study treatment [45].

ASPECT-cUTI baseline characteristics

The ASPECT-cUTI study was a randomized, controlled, phase III trial comparing ceftolozane/tazobactam with high-dose levofloxacin in patients ≥18 years of age who had pyuria and were diagnosed with cUTI or pyelonephritis. Overall, 1083 patients were randomized and baseline characteristics for the microbiological modified intention-to-treat (MITT) population (n = 800) were similar between treatment groups. At baseline, 82.0% and 34.3% of patients had pyelonephritis and mild or moderate renal impairment, respectively [46].

ASPECT-cUTI treatment duration

Both treatments were administered for 7 days (ceftolozane/tazobactam IV 1.5 g/q8h; levofloxacin IV 750 mg/QD) [46].

ASPECT-cUTI efficacy

The ASPECT-cUTI trial demonstrated non-inferiority of ceftolozane/tazobactam to levofloxacin for clinical cure and microbiologic eradication of all baseline uropathogens (76.9% [n = 306/398] vs 68.4% [n = 275/402], 95% confidence interval, 2.3–14.6, respectively) in patients with cUTIs (including pyelonephritis) [46].

The efficacy of ceftolozane/tazobactam for the treatment of cUTI and uncomplicated pyelonephritis has also been corroborated with results from a non-comparative study in Japanese patients [51].

ASPECT-cUTI safety

In the ASPECT-cUTI trial, the incidence of AEs, including serious AEs, was similar between the two treatment groups. AEs occurred in 34.7% (n = 185/533) of patients treated with ceftolozane/tazobactam and in 34.4% (n = 184/535) of patients treated with levofloxacin. Across both treatment groups, the most frequent AEs were headache and gastrointestinal symptoms. Serious AEs occurred in 2.8% (n = 15/533) and 3.4% (n = 18/535) of patients in the ceftolozane-tazobactam and levofloxacin treatment groups [46].

Secondary analysis of ASPECT-cIAI and ASPECT-cUTI

A pooled analysis of data from the ASPECT-cIAI and ASPECT-cUTI studies demonstrated that, in patients with moderate renal impairment, dose-adjusted ceftolozane/tazobactam is efficacious and well tolerated [52]. At baseline, 4.5% (n = 36/806) and 7.3% (n = 58/795) of patients with cIAI and cUTI had moderate renal impairment, respectively. Response rates were higher with meropenem (69%) in patients with moderate renal impairment in the cIAI microbiological intention-to-treat (ITT) population compared with ceftolozane/tazobactam (48%). In the cUTI microbiological MITT population, response rates among patients with moderate renal impairment were 81% and 78% in the ceftolozane/tazobactam and levofloxacin groups, respectively. In a pooled safety analysis, the incidence of treatment-emergent AEs in patients with moderate renal impairment was 58.6% (n = 41/70) in the ceftolozane/tazobactam groups and 64.8% (n = 35/54) in the comparator groups. Irrespective of treatment, clinical cure rates in both studies were lower in patients with moderate renal impairment compared with those who had mild or no renal impairment [52].

Patients with nosocomial pneumonia

More recently, in 2019, ceftolozane/tazobactam was also approved for the treatment of patients ≥18 years of age with HABP or VABP [53].

ASPECT-NP was a phase III, double-blind, non-inferiority, randomized controlled trial that compared ceftolozane/tazobactam with meropenem for the treatment of adults ≥18 years of age with either VABP or vHABP who were intubated and mechanically ventilated (NCT02070757; study design, key outcomes, and secondary analyses are summarized in Table 1) [44,54]. Eligible patients were randomly assigned 1:1 to receive either ceftolozane/tazobactam 3 g (n = 362) or meropenem 1 g q8h for 8–14 days (n = 364) [44].

ASPECT-NP baseline characteristics

Overall, 519 (71%) patients had VABP, 239 (33%) had Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of at least 20, and 668 (92%) were in the intensive care unit (ICU). The most commonly observed causative pathogens at baseline, identified in 511 patients, were Enterobacterales (largely K. pneumoniae and E. coli) and P. aeruginosa, which were isolated from 380 (74%) and 128 (25%) patients, respectively [44].

ASPECT-NP treatment duration

Duration of therapy was comparable in both treatment groups, with a median of 7.7 (interquartile range [IQR] 7.3–7.9) and 7.7 (IQR 7.5–10.7) days in the ceftolozane/tazobactam and meropenem groups, respectively. Length of treatment was similar between groups, regardless of causative pathogens.

ASPECT-NP efficacy

In ASPECT-NP, ceftolozane/tazobactam was shown to be non-inferior to meropenem regarding the primary endpoint of 28-day all-cause mortality in the ITT population (24.0 vs 25.3%, respectively; weighted proportion difference, 1%; 95% CI, -5.1 to 7.4) [44]. Ceftolozane/tazobactam also met the key secondary endpoint of non-inferiority to meropenem for clinical cure at test of cure (TOC) visit (also evaluated in the ITT population): 54.4 versus 53.3%, respectively, with no significant difference between treatment groups [44]. In the clinically evaluable population, clinical relapse at late follow-up was observed in 3% (n = 6/218) versus 5% (n = 10/221) of patients in the ceftolozane/tazobactam and meropenem groups, respectively [44].

Similar frequencies of per-patient clinical cure and mortality rate were observed between treatment groups across key geographical regions and pre-defined patient subgroups, including patients with augmented renal clearance (ARC) [44]. In critically ill patients with ARC, enhanced drug clearance may lead to lower plasma concentrations, shorter drug half-life, and reduced area under the concentration–time curve, potentially leading to therapy failure [55]. This is an important consideration for drugs such as ceftolozane and tazobactam, which are both renally eliminated and for which efficacy is time dependent [56].

Notably, clinical outcomes among patients with renal impairment treated with ceftolozane/tazobactam or meropenem were consistent with those observed in the overall population; however, mortality rates were numerically higher and clinical cure rates were lower in patients with renal impairment in both treatment groups than in those with normal renal function [44,57]. Huntington et al. identified that 28-day all-cause mortality rates for the ceftolozane/tazobactam treatment group versus the meropenem treatment group were generally comparable: 17.6% versus 19.1%, respectively (difference: 1.4%; 95% CI, -5.7 to 8.5) in patients with normal renal function; 36.6% versus 28.6% (difference: -8.0%; 95% CI, -22.0 to 6.5) in those with mild renal impairment; 31.4% versus 38.5% (difference: 7.0%; 95% CI, -16.0 to 30.0) in those with moderate renal impairment; and 35.3% versus 61.9% (difference: 26.6%; 95% CI, -4.9 to 51.6) in those with severe renal impairment, supporting the use of ceftolozane/tazobactam in patients with renal impairment [57].

Overall, per-pathogen clinical cure in the microbiologic ITT (mITT) population was similar between treatment groups for infection with Gram-negative pathogens, with 60.6% (n = 157/259) versus 57.1% (n = 137/240) of patients demonstrating clinical cure in the ceftolozane/tazobactam and meropenem groups, respectively [44]. The frequency of microbiologic eradication of Enterobacterales at TOC in the mITT population was similar between the ceftolozane/tazobactam and meropenem treatment groups (n = 145/195 [74%] vs n = 129/185 [70%], respectively). The frequency of eradication of ESBL-producing Enterobacterales and P. aeruginosa was 67% (n = 56/84) versus 71% (n = 52/73) and 75% (n = 47/63) versus 63% (n = 41/65) in the ceftolozane/tazobactam and meropenem groups, respectively [44].

ASPECT-NP safety

In the safety population of ASPECT-NP, the incidence of AEs, the severity of AEs, and the incidence of AEs leading to study drug discontinuation were similar between treatment groups. This included the proportion of patients experiencing ≥1 AE, which was 86% (n = 310/361) in the ceftolozane/tazobactam group versus 83% (n = 299/359) in the meropenem group. Serious AEs were more common in patients in the ceftolozane/tazobactam group than in those in the meropenem group (42% [n = 152/361] vs 36% [n = 129/359], respectively). The majority of study drug discontinuations related to AEs were due to fatal AEs rather than to investigator decisions (65% [n = 24/37] in the ceftolozane/tazobactam group and 67% [n = 28/42] in the meropenem group). Treatment-related AEs were reported in 11% [n = 38] of patients in the ceftolozane/tazobactam group and 8% [n = 27] in the meropenem group. The most common treatment-related AEs in the ceftolozane/tazobactam group were Clostridioides difficile colitis, abnormal liver function tests, and diarrhea [44].

Secondary analyses of the ASPECT-NP trial

Several post hoc analyses have been performed to determine the effectiveness of ceftolozane/tazobactam in specific patient populations.

Ventilated HABP subgroup

Several studies have suggested that mortality rates associated with vHABP are greater than other types of nosocomial pneumonia, including VABP [58,59]. In the ASPECT-NP trial, vHABP and VABP were pre-defined patient subgroups and pneumonia type was a stratification factor for randomization [60]. At Day 28, mortality rates were highest in patients with vHABP (i.e., patients who require mechanical ventilation subsequent to hospital-acquired pneumonia), at 27.8%, followed by VABP (18.0%; i.e., patients who develop pneumonia following 2 days of mechanical ventilation) and non-ventilated HABP (14.5%) [59]. Thus, the vHABP subpopulation represents a particularly vulnerable population of particular interest for evaluation. In patients with vHABP, the higher mortality expected compared with VABP was seen only in those receiving meropenem (37% [n = 40/108] vHABP vs 20% [n = 52/256] VABP), but not in those receiving ceftolozane/tazobactam (24% for both vHABP [n = 24/99] and VABP [n = 63/263]) [44]. To explore the clinical significance of this outcome, a post hoc multivariable logistic regression analysis was conducted in the vHABP patient subgroup. It was demonstrated that, even when controlling for other factors, ceftolozane/tazobactam use was still associated with a decrease in mortality [60]. In the mITT population, 28-day all-cause mortality was 18.2% (n = 10/55) and 36.6% (n = 26/71) in the ceftolozane/tazobactam and meropenem treatment groups, respectively [60].

Patients failing initial antibiotic therapy

Participants whose prior antibacterial therapy had failed for the current episode of pneumonia at study entry had lower 28-day all-cause mortality rates with ceftolozane/tazobactam versus meropenem treatment in the ASPECT-NP trial (22.6% [n = 12/53] vs 45.0% [n = 18/40], respectively) [61]. To examine this outcome in more detail, a post hoc analysis examining this important pre-defined patient population was conducted [61]. Multivariable regression analysis determined that, after controlling for other factors, the risk of dying after treatment with ceftolozane/tazobactam was approximately one-quarter of that following treatment with meropenem (28-day all-cause mortality; odds ratio [OR] 0.23; 95% CI, 0.08–0.68), further supporting the use of ceftolozane/tazobactam in this patient population [61].

Emergence of resistance during therapy

An exploratory analysis of the ASPECT-NP trial investigated the emergence of non-susceptibility (i.e., lack of sensitivity to specific antibiotics) among P. aeruginosa respiratory isolates after treatment with ceftolozane/tazobactam or meropenem. Emergence of non-susceptibility was not observed among the 59 participants with baseline susceptible P. aeruginosa isolates who received ceftolozane/tazobactam. However, emergence of non-susceptibility was observed in 13 (22.4%) participants with baseline susceptible P. aeruginosa isolates who received meropenem [62].

Per pathogen outcomes

Owing to potential differences in treatment outcomes resulting from causative lower respiratory tract pathogens, efficacy outcomes assessed in the ASPECT-NP trial were also evaluated per-pathogen in a prospective secondary analysis [63]. An analysis of key baseline lower respiratory tract pathogens, including P. aeruginosa and ESBL-producing Enterobacterales, revealed that ceftolozane/tazobactam was comparable to meropenem for 28-day all-cause mortality (P. aeruginosa: ceftolozane/tazobactam 25% and meropenem 20%; ESBL-producing Enterobacterales: ceftolozane/tazobactam 13% and meropenem 29%). In addition, ceftolozane/tazobactam and meropenem were comparable for the endpoint of clinical cure at TOC (P. aeruginosa: ceftolozane/tazobactam 59% and meropenem 59%; ESBL-producing Enterobacterales: ceftolozane/tazobactam 65% and meropenem 62%), as well as microbiologic eradication at TOC (P. aeruginosa: ceftolozane/tazobactam 77% and meropenem 61%; ESBL-producing Enterobacterales: ceftolozane/tazobactam 72% and meropenem 71%) [63].

Treatment of ESBL-producing organisms

The MERINO trial compared piperacillin/tazobactam with meropenem in patients with bloodstream infection caused by ceftriaxone-non-susceptible E. coli or K. pneumoniae [64]. When comparing piperacillin/tazobactam with meropenem on the outcome of 30-day mortality, non-inferiority could not be demonstrated, casting doubt on the use of tazobactam as a β-lactam/β-lactamase inhibitor combination agent for the treatment of any serious infections caused by ESBL-producing pathogens [64,65]. To further examine the use of ceftolozane/tazobactam in nosocomial pneumonia caused by ESBL-producing organisms, the ASPECT-NP trial data in the subset of participants with Enterobacterales isolates (who met criteria similar to those used in the MERINO trial; i.e., ESBL-positive and susceptible to the study drugs) were examined. Overall, 61 out of 726 (8.4%) participants had baseline lower respiratory tract isolates susceptible to both treatments and ≥1 baseline ESBL-positive/AmpC-overproducing Enterobacterales isolate. Subgroup analysis of these 61 participants demonstrated that ceftolozane/tazobactam remains an effective treatment option for HABP/VABP caused by ceftolozane/tazobactam-susceptible ESBL-positive and/or AmpC-producing members of the Enterobacterales [34]. This conclusion is further supported by post hoc analyses of pooled data from the ASPECT-cUTI and ASPECT-cIAI trials, in which high clinical cure rates were observed with ceftolozane/tazobactam therapy for the treatment of infection caused by ESBL-producing Enterobacterales [66].

Outcomes in patients with ARC

A secondary analysis of the ASPECT-NP trial assessed efficacy outcomes in participants with ARC versus those with normal renal function [56]. Patients with ARC versus those with normal renal function treated with either ceftolozane/tazobactam or meropenem had comparable rates of 28-day all-cause mortality (6.7% vs 32.3%, respectively; difference: 25.6%; 95% CI, 5.54–43.84), clinical cure (73.3% vs 61.3%; difference: 12.0%; 95% CI, -11.21 to 33.51), and microbiologic cure (64.5% vs 74.3%; difference -9.8%; 95% CI, -30.80 to 12.00) [34]. Results demonstrated high PTA and confirmed that ceftolozane/tazobactam 3 g q8h is suitable in patients with HABP/VABP (including those with ARC), without the need for dose modifications [56].

Outcomes by degree of respiratory or cardiovascular dysfunction

A sub-analysis evaluating treatment outcomes by degree of respiratory or cardiovascular dysfunction assessed patients based on Sequential Organ Failure Assessment (SOFA) score. The 28-day all-cause mortality rate for ceftolozane/tazobactam versus meropenem was 23.7% and 24.0% (difference: 0.3%; 95% CI, 6.4–6.9) for R-SOFA ≥2 (indicative of severe respiratory failure), 33.3% and 30.3% (difference: -3.0%; 95% CI, 16.4–10.3) for CV-SOFA ≥2 (indicative of shock), and 34.8% and 30.8% (difference: -4.0%; 95% CI, -18.6 to 10.3) for R-SOFA ≥2 plus CV-SOFA ≥2, respectively [67]. Relative efficacy of ceftolozane/tazobactam or meropenem was not affected by the presence of severe respiratory failure or shock, suggesting that either agent may be suitable for use in critically ill patients with vHABP/VABP [67].

Real-world evidence

Studies have substantiated the clinical efficacy of ceftolozane/tazobactam for the treatment of serious infections in various high-risk patient populations. Evidence suggests that similar outcomes can be observed in the real-world setting [68,69]. To summarize all published real-world effectiveness data on ceftolozane/tazobactam would be too extensive for the scope of this review. Two pivotal systematic literature reviews have described evidence at the time of publishing and can be referred to for additional and more in-depth reading. The publications discussed below represent those that were of particular interest in the context of ceftolozane/tazobactam treatment in a clinical setting. The studies discussed were chosen as they comprise sufficiently sized populations of interest and provide additional value and insight into the use of ceftolozane/tazobactam in patients with pneumonia [68,70]. A summary of the studies can be found in Table 2.

A retrospective, multicenter, observational cohort study of patients with drug-resistant P. aeruginosa infection, which included VABP (52%), cUTI (14%), and HABP (13%), demonstrated clinical cure in 81% (n = 81/100) of patients who received ceftolozane/tazobactam compared with 61% (n = 61/100) of those who received a polymyxin or aminoglycoside-based regimen (p = 0.002; OR: 2.72; 95% CI, 1.43–5.17) [71]. After adjusting for differences between the two groups, treatment with ceftolozane/tazobactam was independently associated with clinical cure (adjusted OR: 2.63; 95% CI, 1.31–5.30) [71]. In patients with pneumonia, clinical cure rates for ceftolozane/tazobactam versus polymyxin or aminoglycoside-based therapies were similar to those of the overall cohort (80% vs 56%; p = 0.002). This cohort represented a particularly ill patient population (N = 200), with 69% (n = 138) of those patients residing in an ICU, 63% (n = 126) being mechanically ventilated, and 42% (n = 84) having severe sepsis or septic shock at infection onset [71].

A prospective randomized study in patients with Gram-negative or Gram-positive infections, presenting with febrile neutropenia and fever, showed that those who had received ceftolozane/tazobactam had a higher rate of favorable clinical response at the end of treatment than patients who received standard of care antibiotics (87% [n = 41/47] vs 72% [n = 36/50], respectively) [72]. In addition, superiority tests showed that ceftolozane/tazobactam led to significantly lower rates of clinical failure at TOC (6% [n = 3/47] vs 30% [n = 15/50]; p = 0.003) and late follow-up (9% [n = 4/41] vs 30% [n = 15/50]; p = 0.008) compared with standard of care treatment, respectively [72].

Data from 20 hospitals across the USA were collected from patients (N = 205) with MDR P. aeruginosa infections treated with ceftolozane/tazobactam [69]. Of these patients, 59% (n = 121) had pneumonia and more than half were in the ICU at the time of infection [69]. Overall, treatment with ceftolozane/tazobactam for ≥24 h resulted in clinical success (73.7% [n = 151]) and microbiologic cure (70.7% [n = 145]). In patients with pneumonia, clinical success rates for ceftolozane/tazobactam treatment of VABP and non-VABP were 50.0% (n = 29/58) and 81.0% (n = 51/63), respectively [69].

A systematic literature review assessed published evidence on ceftolozane/tazobactam between 2009 and 2020. The analyses comprised a total of 658 patients who were treated with ceftolozane/tazobactam, with the majority infected with P. aeruginosa pathogens (92.8% [n = 603]); of these isolates, 88.1% (n = 586) were MDR. Assessment of these studies revealed an increase in the proportion of patients receiving the recommended dose of ceftolozane/tazobactam for respiratory infections over time (36.8% in 2017 vs 71.5% in 2020). Clinical success rates observed within the studies (n = 494) ranged from 51.4% to 100%, and approximately 90% of studies reported a 30-day mortality of <30%. When evaluating by infection type, two studies with patients who had nosocomial pneumonia or HABP (n = 35) reported clinical success rates of 75–100%. One study observed a clinical success rate of 100% in two patients with VABP. Across nine studies (n = 409) that included patients with MDR P. aeruginosa infections, clinical success ranged from 61.5% to 100%, and 30-day mortality ranged from 0.0% to 33.3%. When compared with the standard of care antibacterial agents, one study found no significant difference in the rates of clinical cure with ceftolozane/tazobactam versus standard of care (72.6% vs 67.9%; p = 0.683). However, patients who received treatment with ceftolozane/tazobactam had a higher number of comorbid conditions compared with those receiving standard of care, and were significantly more likely to be admitted to the ICU following diagnosis, implying higher rates of severe disease associated with patients in the ceftolozane/tazobactam group [68].

Real-world studies have shown that ceftolozane/tazobactam therapy is effective for patients with comorbidities and P. aeruginosa infection (including MDR P. aeruginosa). In one study, patients with hematologic malignancy and P. aeruginosa infection, who received ceftolozane/tazobactam therapy for 14 days, had significantly lower 30-day mortality and numerically higher clinical cure than those who received other antibacterial agents (5.3% [n = 1/19] vs 28.9% [n = 11/38], p = 0.045; and 89.5% [n = 17/19] vs 71.1% [n = 27/38], p = 0.183, respectively) [73]. In another real-world study (N = 69), the majority of immunocompromised patients treated with ceftolozane/tazobactam for pneumonia associated with MDR P. aeruginosa infection (n = 39) achieved clinical cure (62%), and the overall 30-day mortality rate was 21% [74].

Clinical perspective

Ceftolozane/tazobactam is a useful combination antibiotic in patients with HABP/VABP. There are two clinical conditions for which the use of this antibacterial agent is particularly relevant: patients with vHABP and patients with P. aeruginosa VABP. The ASPECT-NP trial and subsequent analyses demonstrated a benefit when using ceftolozane/tazobactam to treat patients with VABP and vHABP, compared with meropenem [44,67].

Regarding vHABP, many studies have highlighted an association with high mortality rates [29–31]. One recent prospective study in Europe observed that the highest mortality rates occurred in patients with vHABP out of all patients admitted to an ICU with a lower respiratory tract infection [75]. In addition, several published articles have found that patients with poor outcomes typically experience multiple relapses and harbor a selection of resistant strains. The lower mortality rates observed in the ASPECT-NP trial in patients with VABP/vHABP treated with ceftolozane/tazobactam compared with meropenem support the use of ceftolozane/tazobactam in critically ill patients [67].

In patients with HABP and/or VABP who are infected with P. aeruginosa, ceftolozane/tazobactam has been shown to be an effective antibiotic with adequate eradication rates [63], tackling the most concerning problem in patients with this pathogen. International guidelines recommend using 7–8-day antibiotic courses for P. aeruginosa pneumonia [76,77]. In cases of treatment failure, the course of therapy can be prolonged, guided by biomarkers [78]. When using ceftolozane/tazobactam, study results demonstrate a good elimination rate that allows clinicians to implement antimicrobial stewardship strategies of short, but effective, antimicrobial courses [42].

There are some important considerations when using ‘new antibiotics’ in daily clinical practice. We must be careful of the indiscriminate use of antibiotics for patients when the infection is not present. The likelihood of determining a true infection in critically ill patients can be challenging in current practice. However, there are important considerations regarding antibiotic prescriptions that need to be observed in order to match antimicrobial stewardship (AMS) policies. The ‘three Ds’ recommend that dosing should be adequate, duration should be short and de-escalation of treatment should be aggressive. Based on experience in clinical practice, duration of ceftolozane/tazobactam treatment typically spans 7–10 days, used in line with good AMS. In addition to these considerations, the incorporation of adequate clinical parameters, such as good clinical response, and the implementation of molecular testing, are essential to provide information that can help determine the culprit pathogen.

In summary, clinicians welcome ceftolozane/tazobactam as an effective alternative to the antibiotic armamentarium, and its effectiveness can be observed in the treatment of severe healthcare-associated infections affecting critically ill patients with HABP or vHABP.

Conclusion

The effectiveness of ceftolozane/tazobactam has been demonstrated in multiple serious Gram-negative infections, including in patients with cUTI, cIAI, and nosocomial pneumonia. Analyses of specific patient populations have highlighted the suitability of ceftolozane/tazobactam treatment for critically ill patients, including those with altered PK, comorbidities, and infection with MDR pathogens. Given the increase in the prevalence of MDR, access to alternative antibacterial agents, such as ceftolozane/tazobactam, has never been more important.

Future perspective

For the successful treatment of nosocomial infections, such as HABP, vHABP and VABP, prompt administration of effective antibacterial agents is essential. With the increasing worldwide threat of antibacterial resistance, monitoring of pathogenic strains through comprehensive surveillance programs, alongside the continued development of novel antibacterial drugs, should be considered a priority. Ceftolozane/tazobactam is an effective alternative to carbapenems, which should be used with care, taking into consideration the local microbiologic epidemiology. It is encouraging that susceptibility rates observed in real-world surveillance studies and clinical efficacy trials assessing ceftolozane/tazobactam in ventilated patients with pneumonia remain high; however, it is important that the emergence of non-susceptibility after treatment continues to be monitored. With the recent development and effectiveness of β-lactam/β-lactamase combinations, future guidance should consider recommendations on the preferential use of these agents in high-risk patients, where appropriate.